Abstract
Fbxw7, a subunit of the SCF E3 ubiquitin ligase, recognizes oncoprotein substrates and leads to their proteasomal degradation. Fbxw7 acts as a tumor suppressor via inducing apoptosis and growth arrest in various kinds of tumors. To clarify the initiating role in gastric carcinogenesis as well as the histologic characterization of tumor in Fbxw7 allele haploinsufficient mice, we generated Fbxw7 heterozygous knockout mice (Fbxw7+/−) and treated them with chemical carcinogen N-methyl-N-nitrosourea (MNU) at 5–6 weeks of age. We also treated mouse embryo fibroblasts (MEFs) from Fbxw7+/− and Fbxw7+/+ mice with MNU and examined cell DNA damage via comet assay. The protein expression of Fbxw7 and its substrate c-Myc from mouse tumors, as well as human tumors sampled from six patients, were detected by Western blot. As results, the tumor incidence was obviously higher in Fbxw7+/− mice (13/20) than in Fbxw7+/+ mice (6/20) after 35-week observation. Intestinal metaplasia (P = 0.013) and dysplasia (P = 0.036) were more severe in Fbxw7+/− mice than in Fbxw7+/+ mice. The repair potential of DNA damage was suppressed in MEFs from Fbxw7+/− mice after MNU exposure. Increased c-Myc expression was accompanied by decreased Fbxw7 protein expression in tumor tissues from mouse and patients. In conclusion, Fbxw7 haploinsufficiency increased the risk of gastric carcinogenesis induced by MNU, which is associated with the accumulation of DNA damage as well as c-Myc oncoprotein.
Highlights
Gastric cancer is one of the most common cancers worldwide [1]
Fbxw7 haploinsufficiency increased the risk of gastric carcinogenesis induced by MNU, which is associated with the accumulation of DNA damage as well as c-Myc oncoprotein
Fbxw7 gene alteration has been found in a variety of tumors, such as lymphoma, glioma, colorectal cancer and gastric cancer [12, 13, 26, 27]
Summary
Gastric cancer is one of the most common cancers worldwide [1]. It is thought to result from a combined attack by environmental factors and genetic alterations [2]. Activation of oncogenes and silence of tumor suppressors play important roles in gastric carcinogenesis. Most of them have been shown as oncogenes in multiple types of human cancers. A reduced expression of Fbxw is detected in gastric tumors compared to the paired non-neoplastic specimens and is associated with a highly invasive phenotype in gastric cancer cell lines [7, 8]. Fbxw displays a mutation frequency about 6% in multiple human cancers, including gastric cancer [9,10,11]. Genetic inactivation of Fbxw causes chromosomal instability characterized by aneuploidy and micronucleus formation [12] and is associated with the increased rate of radiationinduced tumors [13]. FBXW7 promotes ubiquitination of XRCC4 via lysine 63 linkage to facilitate nonhomologous end-joining, rather than proceeds to XRCC4 degradation [14], while these two pathways of ubiquitination (via K48 www.impactjournals.com/oncotarget and K63 linkage) contribute to the tumor suppressor role of FBXW7 together
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